Sonodynamic therapy with immune modulatable two-dimensional coordination nanosheets for enhanced anti-tumor immunotherap
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Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020 Received: 8 July 2020 / Revised: 18 August 2020 / Accepted: 22 August 2020
ABSTRACT Ultrasound with deep penetration depth and high security could be adopted in sonodynamic therapy (SDT) by activating sonosensitizers to generate cytotoxic reactive oxygen species (ROS). Herein, two-dimensional (2D) coordination nanosheets composed of Zn2+ and Tetrakis(4-carboxyphenyl) porphyrin (TCPP) are fabricated. While exhibiting greatly enhanced ultrasoundtriggered ROS generation useful for noninvasive SDT, such Zn-TCPP 2D nanosheets show high loading capacity of oligodeoxynucleotides such as cytosine–phosphorothioate–guanine (CpG), which is a potent toll like receptor 9 (TLR9) agonist useful in activating immune responses. Highly effective SDT of primary tumors could release tumor-associated antigens, which working together with Zn-TCPP/CpG adjuvant nanosheets could function like whole-tumor-cell vaccines and trigger tumor-specific immune responses. Interestingly, ultrasound itself could strengthen anti-tumor immune responses by improving the tumor-infiltration of T cells and limiting regulatory T cells in the tumor microenvironment. Thus, SDT using Zn-TCPP/CpG nanosheets after destruction of primary tumors could induce potent antitumor immune responses to inhibit distant abscopal tumors without direct SDT treatment. Moreover, SDT with Zn-TCPP/CpG could trigger strong immunological memory effects to inhibit cancer recurrence after elimination of primary tumors. Therefore, the 2D coordination nanosheet may be a promising platform to deliver potent SDT-triggered immunotherapy for highly effective cancer treatment.
KEYWORDS two-dimensional nanosheets, biodegradable, sonodynamic therapy, regulate immunosuppressive TME, immunotherapy
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Introduction
Ultrasound is a kind of mechanical sound wave with periodic vibration at frequencies higher than the upper audible limit of human hearing (> 20 kHz)[1]. While being widely employed for diagnostic imaging in medicine, ultrasound at various frequencies has also been applied for drug delivery or new therapeutic applications [1–3]. Ultrasound at the frequency from 20 to 100 kHz has been utilized to permeabilize the skin and facilitate the delivery of various drugs including chemotherapeutic drugs, hydrocortisone, salicylic acid, oligonucleotides, insulin, and vaccines [4–7]. High intensity focused ultrasound (HIFU) exhibits efficient thermal effects, and thus could be used for cancer ablation treatment in clinic [8–10]. Moreover, ultrasound at harmonically-related frequencies ranging from 0.04–3.00 MHz could activate the sonosensitizers to generate reactive oxygen species (ROS) to induce cancer cell death [11–14]. This therapeutic strategy is typically called sonodynamic therapy (SDT), which derives from photodynamic therapy (PDT) where light is used as the stimulus to activate photosensitizers. Thanks to the low tissue attenuation coefficient and nonradiation, ultrasound penetrates much deeper into t
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